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. 2017 Jan 4;24(2):217–225. doi: 10.1177/1076029616683802

Oral Contraceptives and HRT Risk of Thrombosis

Argyri Gialeraki 1, Serena Valsami 2, Theodoros Pittaras 2, George Panayiotakopoulos 3, Marianna Politou 2,✉
PMCID: PMC6714678  PMID: 28049361

Abstract

Estrogen-containing medication, prescribed either for contraception in women of reproductive age or for prevention of cardiovascular events and osteoporosis as well as for alleviation of symptoms related to menopause, is associated with changes in the hemostatic balance and contributes to increased risk of development of venous thromboembolic complications. This risk is dose and medication dependent, increases with age, congenital and/or acquired predisposition to thrombosis, and mode of administration. This review attempts to summarize the current knowledge regarding the pathophysiology of oral contraceptive (OC) and hormone replacement therapy (HRT) -induced prothrombotic state in women, the risk of thrombosis associated with administration of various commercially available OCs and HRT, the additional risk in women with hereditary or acquired thrombophilia, and the currently available recommendations regarding massive screening of women for thrombophilia prior to initial prescription or continuation of treatment with OCs and HRT preparations.

Keywords: hypercoagulability, thrombophilia, gynecology and obstetrics

Women are exposed to various amounts of estrogen throughout their life. This happens not only naturally due to normal and increased endogenous production during the reproductive period and pregnancy, respectively, but also due to exogenous administration of estrogen containing medication such as oral contraceptives (OCs) and hormone replacement therapy (HRT). Estrogen-containing medication is associated with changes in the hemostatic balance and contributes to increased risk of development of venous thromboembolic (VTE) complications in all women. This effect is exacerbated in women with congenital or acquired predisposition to thrombosis (hypercoagulable state, thrombophilia).

Hormone Therapy and Hemostasis

Recent advances in the elucidation of the hemostatic mechanism allowed a better understanding of the impact of hormone therapy on parameters that affect hemostasis and the contribution to increased risk of VTE. It is well established that the use of OCs confers a series of alterations in procoagulant, anticoagulant, and fibrinolytic pathways.1 The use of OCs is associated with increased levels of plasma-circulating procoagulant factors such as fibrinogen (FI), prothrombin (FII), factors VII, VIII, and X as well as with a moderate decrease of procoagulant factor V (FV), with increased risk for thrombosis.2–4

The anticoagulant pathway is also affected by the use of OCs resulting in decreased plasma levels of naturally occurring inhibitors of hemostasis such as antithrombin and Tissue Factor Pathway Inhibitor (TFPI) and thus with increased risk for thrombosis.5,6 Although OCs seem to trigger a slight increase in protein C biological activity and concentration, this effect is counterbalanced by the concomitant increase of its inhibitors (α1: antitrypsin, α2: macroglobin)5,7 and a pronounced decrease of total and free protein S. The fibrinolytic mechanism is also triggered in women who receive OCs. Increased levels of tissue plasminogen activator and plasminogen as well as decreased levels of plasminogen activator inhibitor 1 are observed. These effects on the fibrinolytic mechanism are partly compensated by increased levels of thrombin-activatable fibrinolysis inhibitor. Nevertheless, it is worth noticing that the clinical implications, if any, of the effect of OCs on the fibrinolytic mechanism are disputed since there is no clear evidence that activation of fibrinolysis is associated with VTE.8

Users of OCs share a common laboratory finding that seems to be interesting—most of them present with acquired resistance to activated protein C (APC-R) with users of the third-generation OCs presenting more pronounced resistance than users of the second-generation products. Resistance to APC is the synergistic result of a series of congenital and acquired factors and contributes to the risk for development of VTE. The effect of OCs on APC-R seems to be associated with changes in sex hormone-binding globulin (SHBG) levels. The SHBG levels increase with increasing concentrations of estrogens while it decreases depending on the degree of antiestrogenicity of the progestogen. Therefore, OCs with “higher estrogenicity” (OCs with high concentration of estrogens or OCs with the third-generation progestogens as well as drospirenone and cyproterone) may cause more pronounced alterations to APC-R and thus contribute to a higher risk for VTE.9,10

Conclusively, increased APC-R mediated not only by decrease in protein S and TFPI but also in SHBG levels has been suggested as a justifiable mechanism of increased risk of thrombosis in women on OCs.11

The route of administration of OCs does not seem to alter that prothrombotic effect. The pathophysiological mechanism that underlies hypercoagulation after OC use seems to be the first-pass effect of estrogens and progestogens through liver since most of caogulation factors and anticoagulants are synthesized in the liver. However, OCs administered with other routes (transdermal patch and vaginal ring) maintain the same prothrombotic effect. Also, the production of Protein S and TFPI by endothelial cells has been a suggested possible mechanism.11

The underlying pathophysiology of the thrombotic risk related to HRTs remains unclear since HRT changes in hemostasis can be both prothrombotic and anticoagulant.12 Acquired APC-R, decrease of Protein C and Protein S, and increased CRP have been proposed as possible mechanisms. Regarding the mode of administration of HRT, transdermal HRT patches seem to have little or no effect on hemostasis variables, activation of the coagulation cascade, or fibrinolysis.13

Oral Contraceptives

Most hormonal contraceptives that are commercially available contain either a combination of an estrogen (mestranol or ethinyl estradiol) and a progestin or exclusively progestin. The first pills that were approved in the 60 seconds contained 150 µg of mestranol.14 Later, products containing lower concentration of mestranol (50 µg) were found to be equivalent to those containing 35 µg of ethinyl estradiol,15 the active metabolite of mestranol which is synthesized in the liver.16 The estrogen content of OCs has been further reduced over the last decades aiming at the minimization of adverse effects attributed to them. Currently available OCs contain only 15 µg of ethinyl estradiol. Progestins are classified according to the decade of initial production, as the first (60 s; norethynodrel), second (70 s; levonorgestrel), or third (80 s and 90 s; estodene and desogestrel, respectively) generation.17 There are also OCs that contain the antiandrogen cyproterone acetate or the antimineralocorticoid drospirenone (the fourth-generation progestogen).18

Very early use of OCs was associated with an increased risk of VTE. The most frequent manifestations of VTE are deep venous thrombosis (DVT) and pulmonary embolism (PE). However, more rare thrombotic events such as upper-extremity and intraabdominal thrombosis, cerebral sinus thrombosis, and superficial venous thrombophlebitis have also been observed in women who use OCs.19 The risk of thrombosis attributed to OC use has been investigated by numerous studies.20–25 The majority of these studies investigated the dose-dependent effect of estrogen content of OC pills on the development of VTE. The results suggested that the risk is double in women who receive pills containing higher doses of estrogens. The risk for VTE is higher for OCs containing 50 μg ethinyl estradiol compared to those with <35 μg, and OCs containing >30 μg ethinyl estradiol are associated with higher risk than those with 20 μg.20,24 The risk associated with products containing <20 μg ethinyl estradiol remains to be estimated.20,23 The venous thrombotic risk of OCs and the effects of estrogen dose and progestogen type are summarized in the results of the MEGA case–control study.26 Although there are studies that failed to confirm this dose-dependent effect,27–29 it seems that the use of OCs (that contain >20 μg ethinyl estradiol) is associated with 3- to 6-fold increase of the risk of VTE. This increase reflects a low absolute risk of VTE that is estimated to be 1 to 3 cases per 10 000 women-years.

Women aged >40 years who receive OCs have been found to be at higher risk of VTE compared to younger ones.23 This correlation probably reflects the fact that age is a strong and independent prognostic factor for the development of thrombosis.

Moreover, the risk for development of VTE is higher during the first 6 to 12 months following the initiation of treatment, especially among the first-time users. This risk appears to increase from the fourth month of administration, remains stable during the exposure period, and disappears 3 months after discontinuation.23,24,30 The risk of VTE upon reexposure to OCs in women, who had to discontinue treatment, is comparable to that observed in the first-time users.31

The type and strength of progestins contained in OCs was initially thought not to be associated with the risk of VTE. However, most of the studies noted that users of the third-generation OCs experienced higher (but not always statistically significant) risk compared to the second-generation users. A number of case–control studies demonstrated that OCs containing the third-generation progestogens further increased the risk of VTE 1.5- to 3-fold as compared to OCs containing the second-generation progestogen levonorgestrel.23,31–34 The results of several analyses and meta-analyses concluded that there is a real, definite but small difference in the risk between the second- and third-generation OCs. Cyproterone acetate and drospirenone-containing OCs seem to confer the same risk as the third-generation OCs.35

Recent data regarding the impact of OCs on the development of VTE suggest that all currently available products are associated with increased risk. This effect is dose dependent with OCs containing 30 to 35 μg ethinyl estradiol and either gestodene or desogestrel, cyproterone acetate, and drospirenone exerting similar effect which is 50% to 80% higher than the risk with levonorgestrel.19

The effect of OCs in the development of arterial thrombosis has also been investigated.36 The extent of the risk is not clear due to low incidence of arterial disease among young women. Additionally, the small number of arterial events in young women does not allow the reliable estimation of the impact of various hormonal content of different OCs.37 A Cohrane network meta-analysis including data from 24 studies concluded that OCs are not associated with higher risk for myocardial infarction (MI) or stroke. Further analysis of the data suggested that although the risk was not affected by either progestogen type or progestogen generation, it seemed to be dependent on estrogen concentration with higher doses conferring a higher risk.37

Thus, the combination of OCs containing the second-generation progestin (levonorgestrel) and 30 μg of estrogen that are associated with reduced risk for VTE is the safest choice for the prevention of both venous and arterial events and should be preferred as medication especially in the first-time users.38

Progestin-Only Contraceptives and Thromboembolism

Progestin-only contraceptives (POPs) can be administered orally, by injection or as implantable devices. The association between the use of oral POPs and the risk of development of VTE has been thoroughly investigated in several case–control studies. Unanimous results suggest that there is not statistically significant association between the use of POPs and VTE.39

Additionally, the use of oral or injectable progestin-only was associated with little or no increased risk of VTE, in a case–control study.40 Finally, a recent study confirmed that levonorgestrel-releasing intrauterine devices (IUDs) are not associated with high risk of VTE.6 Limited and anecdotal data support that pure progestin contraceptives are associated with lower risk of VTE than OCs, although this observation has not been confirmed so far by studies comparing directly these 2 categories (Table 1).

Table 1.

Hormonal Treatments Are Depicted in Descending Order of Thrombogenicity.

Hormonal Treatment Risk of Thrombosis
First-generation OCs (the progestins noretynodrel, norethisterone, norethisterone acetate, and ≥50 µg ethinyl estradiol) 6-12/10 000 women
Third-generation OCs (the progestins desogestrel or gestodene norgestimate <50 µg ethinyl estradiol) 9-12/10 000 women
Fourth-generation OCs (the progestin drospirenone, dienogest, or nomegestrol acetate <50 µg ethinyl estradiol) Similar
Second-generation OCs (the progestins norgestrel or levonorgestrel and <50 µg ethinyl estradiol) 5-7/10 000 women
Progestin-only (norethisterone, ethynodiol diacetate, levonorgestrel, desogestrel, lynestrenol) 2-3/10 000 women
 Oral contraceptives
 Injectable
implantable intrauterine devices (IUDs) with progestins (levonorgestrel) 2/10 000 women
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Abbreviation: OCs, oral contraceptives.

On the other hand, women who receive POPs but in the context of a therapeutic regime are exposed to 5- to 6-fold increased risk for VTE when compared to women who are not exposed to such products. This finding may reflect either a dose-dependent effect of progestins that are used for therapeutic purpose (higher dose) or an age-dependent effect since women who use therapeutic regimen are older and thus are at higher risk of developing VTE.41,42

Progestin-only products should be considered for women >40 years who are at higher risk for thrombosis (ie, history of VTE) as well as for younger women with other hereditary or acquired thrombophilia.43 Nevertheless, the safety use of POPS in such cases needs to be validated/confirmed in large epidemiological studies.

OCs and Thrombophilia

Several studies have evaluated the association between OCs and development of VTE in women who have known hereditary thrombophilia.20,23,27,44–50 The risk of VTE in women users of OCs who are carriers of FV Leiden (the more frequent cause of hereditary thrombophilia present in 5% to 8% of Caucasians) is 35- to 99-fold higher than in women who are neither users of OCs nor carriers of this prothrombotic mutation.27,44,47,48,50 Similarly, the risk for FII G20210A carriers (the second cause of hereditary thrombophilia present in 2% to 4% of Caucasians) is 16-fold increased.46 This increase is supradditive, meaning that the neat probability of developing VTE is much higher than that calculated by simply adding all individual risk factors. The risk is much higher during the first 12 months of OC use and seems to be even higher when OCs contain the third-generation progestins.30 Consequently, women carriers of either FV Leiden or FII G20210A should be advised not to use OCs. However, it must be noted that although the relative risk for VTE in these women is extremely high, the estimated residual risk remains relatively low (28-50 cases per 10 000 women-years).

The risk of VTE in women users of OCs who are carriers of deficiencies of the naturally occurring inhibitors of the coagulation (antithrombin, protein C, and protein S) is 2 to 9 times higher than that observed in women carriers of these deficiencies who do not use OCs, and this finding is associated with a residual 4% annual risk.50 It is worth noticing that these abnormalities are very rare (they account for a total prevalence of <1% in the general population) and are accompanied by more severe thrombotic complications that usually develop in younger age.

Controversies in Treatment

The guidelines published by the Royal College of Obstetricians and Gynecologists advise that the use of OCs in women with known thrombophilia exposes them to nonacceptable risk, and accordingly the use of OCs should not be recommended to women carriers of such deficiencies.51 Oral contraception is contraindicated not only in women with any kind of thrombophilia but also in those with previous thrombosis regardless of the thrombotic event (DVT and PE) and the anticoagulation treatment as well as in women who receive long-term anticoagulation treatment for VTE, according to the World Health Organization guidelines.38

Nevertheless, a recent study has shown that the use of OCs was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The risk was similar for estrogen-containing and progestin-only therapy.52

However, there are cases that OC use should be considered. In such cases, the evaluation of the total risk of VTE takes into account several parameters such as:

Genetic background of thrombophilia—Women with severe thrombophilia (deficiencies of the naturally occurring inhibitors of the coagulation antithrombin, protein C, protein S, FV Leiden, and FII G20210A homozygotes) are at higher risk of developing VTE than women carriers of mild thrombophilia (FV Leiden, FII G20210A carriers).53

Method of contraception—The risk of VTE associated with the use of OCs is much higher compared to the risk associated with the use of levonorgestrel-containing IUDs as well as with the use of intrauterine spirals and condoms which have no effect on the risk.53 The additional risk of VTE is associated with acquired risk factors for thrombosis such as adiposity, diabetes, smoking, hypertension, or polycystic ovary syndrome.43 A clinical history should be taken to identify any relevant medical conditions which may influence contraceptive choice.

The additional risk of VTE is associated with a pregnancy due to ineffective contraception—The effectiveness of OCs is very high so that the possibility of an undesirable pregnancy is significantly lower than that observed with the use of intrauterine spirals and condoms.54

Both pregnancy and use of OCs are independent risk factors for the development of VTE in women with thrombophilia. However, the risk of thrombosis during pregnancy and puerpartum is more pronounced (16-fold, 95% CI: 8.0-32.2) than the risk observed for users of OCs (2.2-fold, 95% CI: 1.1-4.0) both in women who were not carriers of thrombophilia and in women carrying 1 or 2 thrombophilic genes.5

Conclusively, women carriers of thrombophilia are encouraged to use a contraceptive method that combines high effectiveness regarding birth control and acceptable risk for VTE development. The use of POC seems to be a safe method of birth control, according to the current guidelines. The IUDs including those which elute progestin remain an alternative option related with lower risk for thrombosis.55

The OCs have also been used to treat other medical conditions such as polycystic ovary syndrome, menstrual cycle disorders, ovarian cysts, or dysmenorrhea. If OCs have to be prescribed in women with thrombophilia and the above-mentioned disorders when the benefit of the treatment outweighs the possible risk of thrombosis, the use of progestin only OCs seems a reasonable choice.

Should We Test for Thrombophilia

Unjustified routine massive screening for thrombophilia prior to the use of hormonal contraceptives is not recommended. Apart from cost-effectiveness studies, the main argument that further pleads for this statement is the fact that the majority of VTE events develop in women who test negative for thrombophilia and as a consequence a negative result might falsely dichotomize women and reassure noncarriers women that using OCs is free of VTE complications for them.

For women with a family history of VTE, a negative thrombophilia screen does not necessarily exclude all thrombogenic mutations. Thus, a previous family history of VTE remains an important risk factor, regardless of the results of thrombophilia studies.18

Unselected screening for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia who are contemplating the use of estrogen is not recommended. Regarding mild thrombophilia carriers, a large number of women needs to be tested and advised to abstain from OCs use in order to prevent 1 single thrombotic event. Thus, there is no strong indication for testing all asymptomatic women with family history of VTE associated with mild thrombophilia.56

Nevertheless, thrombophilia testing prior to administration of OCs might be useful in asymptomatic relatives of carriers of severe thrombophilia (AT/PrC/PrS deficiency, homozygosity for FV Leiden/FII G20210A).

Hormone Replacement Therapy

Hormone replacement therapy was initially introduced in the 60 seconds for postmenopausal women in order to prevent cardiovascular events and osteoporosis as well as to alleviate symptoms related to menopause. However, current data point out that HRT-associated risk for VTE, cardiovascular disease, and breast cancer counterbalances the benefits from the reduction of osteoporosis and prevention of colorectal cancer.57 Additionally, HRT does not seem to improve the quality of life in postmenopausal women without clinical symptoms, so nowadays it is proposed that HRT should be a therapeutic choice only for postmenopausal women who need to control clinical symptoms.58

Three regimes of HRT are currently available: pure estrogen and combination of estrogens with either continuous or cyclic use of progestin.59 The therapeutic approach of choice for women who retain their uterus is the combination of estrogen with progestin. Pure estrogen HRT should be restricted to women with hysterectomy since it has been associated with increased risk of thickening (hyperplasia) and cancer of the endometrium. The different estrogen types used for HRT are 6-fold less potent than the ethinyl estradiol used for OCs.

Conjugated equine estrogens (CEE) combined with bazedoxifene, a selective estrogen receptor, have also been proposed as an alternative for postmenopausal women with a uterus, in order to avoid progestin containing pills, in cases that progestin administration is contraindicated.60

Oral HRT and VTE

Women who receive HRT are exposed to 2- to 4-fold increased risk of VTE compared to nonusers according to the results of several studies.57,61–71 Although these studies differ in methodology and their results cannot be directly compared, 2 randomized controlled studies including 2500 (Heart and Estrogen/progestin Replacement Study) and 16 000 patients (Women’s Health Initiative)57 respectively, provide very useful information.63 The results of both studies confirmed that HRT is associated with increased risk not only for VTE but also for cardiovascular events (arterial thrombosis) and thus overturned the original hypothesis based on observational studies which was suggesting that HRT exerted protective effect on the development of cardiovascular disease. The relative increased risk is translated to an absolute risk of 2.3 cases per 1000 women-years, provided that HRT is associated with a favorable risk/benefit relation.

The risk of HRT-associated thrombotic events such as DVT or PE has been evaluated by several studies.57,63,66,67 Although results point out a definite association between HRT and increased risk for DVT, results regarding PE are contradictory. According to a meta-analysis including results on 20 000 women and 4 studies, the estimated risk of PE in HRT users was 2.16 but with the limitation that existing randomized trials are too small to describe reliably the effect of HRT on such important but rare conditions.72 The only randomized study comparing HRT to placebo in 140 women with previous history of VTE terminated early due to the high incidence of VTE in the HRT group compared to the placebo group (10.7% vs 2.3%, respectively).73

The association between the composition of HRT products and risk for VTE has been investigated in many studies. Regarding the type of estrogen, both esterified estrogen (EE) and CEE are associated with a significant risk for VTE although the risk seems to be less for the former. Combined therapy, that is addition of progestogen to estrogen, seems to be associated with an increased risk when compared to estrogen alone in most studies, nevertheless a recent review and meta-analysis failed to document a significant additional risk when progestogen is added to estrogen.71,74,75

The thrombotic risk of the HRT progestogen type is not yet elucidated and needs to be confirmed in future studies. The use of transdermal HRT is not associated with significantly increased risk for VTE development.62,76,77 However, even if the use of transdermal HRT seems to be a safer choice than oral HRT for the short-term management of symptoms in postmenopausal women, the long-term effects on the cardiovascular system have not been investigated yet. Epidemiological and biological findings support the cost-effectiveness and safety of transdermal estrogens in women at high risk for VTE (ie, increased body weight, age >60, history of VTE).78 The safety of transdermal HRT in women with any kind of hereditary thrombophilia or in those with a previous thrombotic event remains to be evaluated.

Phytoestrogens may have some beneficial effect on the management of menopause-related symptoms; however, there are not sufficient data available on possible side effects associated with their use. Additionally, some phytoestrogens have selective “estrogen-receptor modulator-like” properties. The fact that some selective modulators of estrogen receptors have been associated with increased risk of VTE raises the possibility that phytoestrogens may not be a safer choice.79

The risk of VTE attributed to HRT is greater during the first 6 to 12 months of use and gradually decreases or even disappears with prolonged use.57,62,64,65,67,71 The effect of short-term use (few months) of HRT in postmenopausal women with clinical symptoms on the development of VTE is unclear. However, short-term use may still be associated with unfavorable risk/benefit relationship for the development of VTE since the risk is higher during the first months of use.80

Recent data from the Cohrane database that evaluated results from 40 410 postmenopausal women suggest that HRT does not provide protection against all-cause mortality, cardiovascular death, MI, ischemic stroke, or revascularization.81 Both PE and VTE events are increased in postmenopausal women receiving HRT compared to controls (relative ratio: 1.81 vs 1.92, respectively). A subgroup analysis revealed that women who started HRT early (<10 years postmenopause) had lower mortality rates and cardiovascular events compared to women who started late (>10 years) although they were still at increased risk compared to women either on placebo or at no treatment. The fact that oral HRT increases the risk of first VTE advocates against the use of HRT in women with prior history of thrombosis.73

HRT and Hereditary Thrombophilia

The risk of development of VTE in women with thrombophilia who receive HRT has been investigated by several case–control studies. In a multicenter study,82 the presence of FV Leiden conferred a 3.4-fold increased risk (95% CI: 2.0-5.8), and FII G20210A was associated with a 4.8-fold increased risk (95% CI: 2.5-9.4) of VTE, in postmenopausal women. After adjusting for confounding factors, the combination of a prothrombotic mutation and oral estrogen resulted in 25-fold increased risk of VTE when compared to nonusers of HRT who had no genetic predisposition to thrombosis (95% CI: 6.9-95.0). The risk of VTE was associated with oral rather than transdermal estrogen (odds ratio [OR] 4.3, 95% CI: 2.6-7.2 vs OR 1.2, 95% CI: 0.8-1.7, respectively). The use of transdermal estrogens had no effect on the risk of VTE compared to nonusers of estrogens in women with thrombophilia.

A population-based case–control study that investigated the risk for VTE in postmenopausal women with known thrombophilia who were also exposed to either CEE or EE concluded that the presence of FV Leiden and FII G20210A contributes a 9-fold increased risk. However, the use of EEs is associated with less risk than the use of CEEs in these women (OR 2.1, 95% CI: 0.6-6.8 vs OR 9.1, 95% CI: 4.5-18.2, respectively).

The risk of VTE in HRT users who were FV Leiden carriers has been also evaluated in women with coronary disease. The risk was 14.1-fold higher compared to the risk calculated for noncarrier placebo users who served as control group. The estimated absolute incidence of VTE in FV Leiden carriers treated with HRT was 15.4/1000 per year compared to 2.0/1000 per year in controls. The results of the study suggested that FV Leiden testing could be cost-effective in women with coronary disease or before prescribing HRT.83

How I Treat Women With Thrombophilia

Prescription of HRT should be avoided in asymptomatic women with high-risk thrombophilia (deficiency of AT, PrC, and PrS) who have been identified after screening due to family history of VTE. There is not enough evidence to suggest total avoidance of HRT for carriers of mild thrombophilia. The presence of other risk factors such as severity of symptoms, baseline risk of VTE, breast cancer, lipid status, smoking, and obesity should be taken into consideration prior to counseling these women to avoid HRT. If HRT is the only choice for some women, it is necessary to inform them regarding the potential risk of VTE and of the use of transdermal HRT or alternative therapy to relieve the symptoms.84

Should We Test for Thrombophilia

No recommendation is currently available for massive screening of women for thrombophilia prior to initial prescription or continuation of treatment with HRT preparations since the absolute risk of HRT-associated VTE is relatively small. Cost-effectiveness studies concerning screening of women for thrombophilia prior to prescription of HRT point out that the most effective method is the one that recommends evidence-based testing only in women with positive family history of thrombosis.84

Conclusively, the major challenges for the future are the further elucidation of the pathophysiology of hormone-related VTE, the development of new products, and delivery methods, but more important is the improvement of the techniques that stratify individual risk, with the identification of confounding factors that differentiate individual response to hormone treatment.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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